The effectiveness and value of bempedoic acid and inclisiran for heterozygous familial hypercholesterolemia and secondary prevention of ASCVD

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Agboola, McKenna, and Pearson are employed by ICER. Lin and Kazi received funding from ICER for work on this report.

necessary, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is recommended. 9 A new option for lowering cholesterol is bempedoic acid (combined with ezetimibe [Nexlizet] or without ezetimibe [Nexletol], Esperion Therapeutics, Inc.), which was approved by the US Food and Drug Administration (FDA) in February 2020. Bempedoic acid is an inhibitor of adenosine triphosphate (ATP) citrate lyase that lowers LDL-C by reducing cholesterol synthesis upstream of HMG Co-A reductase (statins) and upregulating LDL receptors. 10 Another new lipid-lowering agent, inclisiran (Novartis), is currently under FDA review. Inclisiran is a double-stranded small interfering RNA agent that lowers cholesterol through targeting and inhibiting hepatic PCSK9 synthesis. 11 The Institute for Clinical and Economic Review (ICER) conducted a systematic literature review and cost-effectiveness analysis to evaluate the health and economic outcomes of bempedoic acid and inclisiran. In this report, we present the summary of our findings and highlight the policy discussion with key stakeholders held at a public meeting of the Midwest Comparative Effectiveness Public Advisory Council on February 5, 2021. The detailed report is available at https://icer. org/wp-content/uploads/2020/10/ I C E R _ H i g h-C h o l e s t e r o l _ F i n a l-Evidence-Report_030221.pdf.
Atherosclerotic cardiovascular disease (ASCVD) encompasses a set of chronic conditions that includes coronary artery disease, peripheral artery disease, cerebrovascular disease, and aortic atherosclerotic disease. In the United States, ASCVD affects approximately 1 in 10 people; represents a high risk for future major adverse cardiovascular events (MACE), such as heart attacks and strokes; and is the leading cause of death. 1,2 Heterozygous familial hypercholesterolemia (HeFH) and other conditions that cause very high levels of lowdensity lipoprotein cholesterol (LDL-C) are associated with a high risk of premature ASCVD and MACE. 3 Although HeFH is relatively common-affecting approximately 1 in 250 people in the United States-several studies have reported that the condition is still underdiagnosed and undertreated, particularly among women, Blacks, and Asians. [4][5][6] LDL-C reduction is mainly achieved by high dose or maximally tolerated statin therapy. 7,8 For patients who continue to have LDL-C levels at or above 70 mg/dL, the addition of ezetimibe is recommended as second-line therapy, and if further LDL-C reduction is in extremity, muscle spasms, and tendon rupture); hyperuricemia; gout; elevated liver enzymes (ALTand AST); and changes in renal laboratory parameters (eg, glomerular filtration rate and blood creatinine level).
Inclisiran. We identified three phase 3 RCTs of inclisiran vs placebo, 2 of which were conducted in patients with established ASCVD or ASCVD risk equivalent 16 and 1 in patients with HeFH. 11 All patients were on maximally tolerated lipidlowering therapy.
Meta-analyses of the 3 RCTs (N = 3,660) showed that inclisiran therapy decreased LDL-C levels by 51% from baseline (mean difference = −50.5, 95% CI = −45.5 to −55.5) compared with placebo after 77 weeks of treatment. 11,16 A similar level of LDL-C reduction was observed in the study conducted exclusively in patients with HeFH (N = 482). 11 Inclisiran also improved other lipid parameters compared with placebo, including an increase in HDL cholesterol and reductions in PCSK9, total cholesterol, non-HDL cholesterol, apolipoprotein B, and lipoprotein(a). Clinical outcome studies of inclisiran are also ongoing. Meta-analysis of prespecified exploratory cardiovascular endpoints reported in the phase 3 trials showed a lower rate of the composite cardiovascular outcome (cardiovascular mortality, cardiac arrest, non-fatal myocardial infarction, or stroke) with inclisiran compared with placebo (RR = 0.76; 95% CI = 0.60-0.96). 11,16 The rates of cardiovascular death and all-cause mortality were similar between treatment arms.
Overall, a similar incidence of AEs, serious AEs, and discontinuation were observed between treatment groups. The most common AE with inclisiran was injection site reaction, which occurred in 5.4% of patients vs 0.8% in the placebo group. 11,16

LIMITATIONS OF CLINICAL EFFECTIVENESS
Efficacy data on bempedoic acid and inclisiran are limited to short-term LDL reduction; long-term effect on clinical outcomes has yet to be established for either drug. Bempedoic acid blocks cholesterol synthesis upstream of statins, but it remains to be seen whether the degree of LDL-C lowering observed will translate into a similar degree of reduction in MACE rates as statin drugs. Additionally, bempedoic acid's safety profile raises important questions about whether the increased risk of hyperuricemia and gout, as well as a risk of tendon rupture, seen in the RCTs will be important real-world problems. For inclisiran, although the degree of LDL-C lowering appears to be in the same general range as found for PCSK9 inhibitors, whose mechanism of action lies along the same biochemical pathway, there remains uncertainty whether this will translate into a reduction in MACE rates that are more comparable to those seen with PCSK9

CLINICAL EFFECTIVENESS
We conducted pairwise meta-analyses on each drug separately. We did not attempt to compare these treatments with each other because of key differences across trials in patient characteristics and trial design. Additionally, we did not pursue a quantitative indirect comparison of inclisiran with PCSK9 inhibitors because trials evaluating the impact of inclisiran on cardiovascular outcomes have not been completed.
Bempedoic Acid. We identified 5 pivotal phase 3 randomized clinical trials (RCTs) of bempedoic acid with or without ezetimibe. 10,[12][13][14][15] Four studies examined bempedoic acid vs placebo, including 2 RCTs in patients with ASCVD or HeFH who required further LDL-C lowering despite being on maximally tolerated statin therapy 10,14 and 2 RCTs in patients with ASCVD, HeFH, or hypercholesterolemia who were deemed to be statin intolerant, defined as the inability to tolerate trials of at least 2 statins. 12,15 The fifth RCT examined the combination pill bempedoic acid/ezetimibe vs bempedoic acid alone, ezetimibe alone, and placebo in patients with ASCVD, HeFH, or with multiple risk factors for cardiovascular disease while on maximally tolerated statins. 13 Meta-analyses of the 5 RCTs (N = 3,924) showed that bempedoic acid provided an overall 19.5% decrease in LDL-C after 12 weeks of treatment (I 2 = 69%, P < 0.01) compared with placebo. 10,[12][13][14][15] In patients with statin intolerance (N = 614), a larger LDL-C reduction was observed with bempedoic acid compared with placebo (24.6% vs 17.7%; test for subgroup difference, P = 0.05). 12,15 Bempedoic acid also improved other lipid parameters, including significant reductions vs placebo in total cholesterol, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, and highsensitivity C-reactive protein. Two of the RCTs presented data on cardiovascular events and mortality at 52 weeks. 10,14 Meta-analyses of these studies for these endpoints found relative risks above 1 for all-cause mortality (rate ratio [RR] = 2.25; 95% CI = 0.76-6.67) and cardiovascular mortality (RR = 1.52; 95% CI = 0.41-5.70), but these studies were not powered to examine these endpoints, and numbers of patients with these outcomes were very small. 10,14 Larger ongoing clinical outcome studies will assess these outcomes to evaluate fully how the reduction in LDL-C with bempedoic acid translates into patient-centered outcomes.
Data on adverse events (AEs) from existing trials show that more AEs were associated with bempedoic acid than placebo (24.1% vs 20.3%, P = 0.01). 10,12,14,15 AEs that occurred with more frequency in the bempedoic acid group than the placebo group were muscle-related events (eg, pain In the model, the relative effects of bempedoic acid/ ezetimibe and of inclisiran on LDL-C were "mapped" into a population representative of patients with ASCVD. Population characteristics were estimated from the National Health and Nutrition Examination Survey of US adults aged 35 years and older who have previous ASCVD and an LDL-C level of at least 70 mg/dL on statin therapy. 17 The key input for the effectiveness of each drug was the percentage of reduction in LDL-C achieved at the primary endpoint among individuals receiving the therapy based on the meta-analyses of key clinical trials previously described. The LDL-C reduction observed with each drug was translated into reduction in MACE based on previous evidence for statin therapy, a key assumption given the absence of outcomes data. 18 Full details on ICER's cost-effectiveness analysis and model are available on ICER's website at https://icer.org/ wp-content/uploads/2020/10/ICER_High-Cholesterol_ Final-Evidence-Report_030221.pdf. Model results found that bempedoic acid/ezetimibe would produce modest improvements in clinical outcomes but that, at current estimated prices net of rebates and other concessions, the drug is unlikely to achieve commonly cited cost-effectiveness thresholds of $100,000-$150,000 per quality-adjusted life-year (QALY) or per equal value of life-years gained (evLYG; Table 1). For inclisiran, at a placeholder price of $5,644 per year, set equivalent to the current average annual price for PCKSK9 inhibitor drugs, inclisiran approaches a cost-effectiveness threshold of $150,000 per QALY and falls slightly below $150,000 per evLYG (Table 1). Both treatments had better cost-effectiveness in higher risk subgroups, such as patients who are statin intolerant or who have HeFH.

LIMITATIONS OF THE COST-EFFECTIVENESS MODEL
As previously noted, clinical outcome studies on bempedoic acid/ezetimibe and inclisiran are ongoing. Thus, the LDL-C reductions observed with each drug in the short-term inhibitors or with statins. Finally, the trials of bempedoic acid and inclisiran did not include many patients from minority populations, who are disproportionately affected by ASCVD, and trials of bempedoic acid included very few patients with HeFH, raising concerns about the generalizability of the findings.

LONG-TERM COST-EFFECTIVENESS
We evaluated the cost-effectiveness of bempedoic acid and inclisiran in patients with established ASCVD from a US health care sector perspective using a de novo statetransition Markov decision-analytic model. Our analyses compared each treatment plus ezetimibe and maximally tolerated statin therapy vs ezetimibe and maximally tolerated statin therapy only. The choice to model both treatments against statins plus ezetimibe stands in contrast to realworld data suggesting use of ezetimibe at less than 10% among patients who require further LDL-C lowering after statins. However, ezetimibe is now fully endorsed by clinical guidelines, and it has demonstrated mortality benefits.
Bempedoic acid is a more expensive oral alternative, and now that it is available, it is likely that more payers will require ezetimibe trials before approving insurance coverage for bempedoic acid or for PCSK9 inhibitors and inclisiran. Moreover, we believe that the true incremental value of these 2 new agents, and their associated valuebased price calculations, should be framed against the clinical and economic outcomes of statins plus ezetimibe.
For bempedoic acid, we chose to evaluate the costeffectiveness of its use in combination with ezetimibe (bempedoic acid/ezetimibe), since it is priced the same as bempedoic acid alone and so would be expected to dominate bempedoic acid in any economic evaluation. Separate evaluations included subgroups of patients with HeFH, those intolerant to statins, and "high-risk" patients who have had acute coronary syndrome in the past year. The model used a lifetime time horizon, and costs and outcomes were discounted at 3% per year.  The Midwest CEPAC panel also voted on "contextual considerations" and "potential other benefits or disadvantages" as part of a process intended to signal to policymakers whether there are important considerations when making judgments about long-term value for money not adequately captured in analyses of clinical and/or cost-effectiveness. The results of these votes are shown in Tables 2 and 3. They highlight several factors beyond the results of costeffectiveness modeling that the CEPAC panel felt were particularly important for judgments of overall long-term value for money.
The culminating vote of the CEPAC panel, intended to reflect its integration of the relevant elements of the value assessment framework, was on the "long-term value for money." A majority (13/14) of the panel members voted that the long-term value for money of combination pill bempedoic acid and ezetimibe plus usual care is low compared trials were translated into MACE reduction in our model based on previous evidence for statin therapy. If outcomes trials demonstrate that these relationships are substantially different, it will change the results of our analyses. Additionally, our economic evaluation assumes that statinintolerant patients are on no statin therapy, although real-world data suggest that many patients with statinassociated side effects can tolerate statins at low doses. Therefore, our findings would overestimate the clinical and economic benefit of lipid lowering if extrapolated to all patients with statin-associated side effects in real-world settings. Finally, our model did not examine primary prevention populations, which are at lower baseline risk for MACE than patients with established ASCVD.

Policy Discussion
The Midwest Comparative Effectiveness Public Advisory Council (CEPAC) is one of the independent appraisal committees convened by ICER to engage in the public deliberation of the evidence on clinical and cost-effectiveness of health care interventions. The Midwest CEPAC is composed of medical evidence experts, including practicing clinicians, methodologists, and leaders in patient engagement and advocacy. Their deliberation includes input from clinical experts and patient representatives specific to the condition under review and formal comments from manufacturers and the public. A policy roundtable concludes each meeting during which representatives from insurers and manufacturers join clinical experts and patient representatives to discuss how best to apply the findings of the evidence to clinical practice, insurance coverage, and pricing negotiations.
The ICER report on treatments for HeFH and secondary prevention of ASCVD was the subject of a Midwest CEPAC meeting on February 5, 2021. Following the discussion, the CEPAC members deliberated on key questions raised  with the addition of ezetimibe alone (eg, ≥ 25% above their LDL-C goal), payers should allow coverage for the with usual care alone in all patients with established ASCVD and/or HeFH, a vote dominated by the uncertainty regarding clinical benefit and the base case cost-effectiveness above $150,000 per QALY. At the current assumed price of inclisiran, a majority (10/14) of the panel judged that inclisiran represents a low long-term value for money in all patients with established ASCVD and/or HeFH when compared with usual care alone, a vote also colored by the lack of outcomes data and an estimated cost-effectiveness at the upper boundary of traditional cost-effectiveness thresholds.

Votes on Contextual Considerations and Potential Other Benefits or Disadvantages for Any New Effective Treatment for the Secondary Prevention of ASCVD
The policy roundtable discussion explored how best to translate the evidence and additional considerations into clinical practice, pricing, and insurance coverage policies. The full set of policy recommendations can be found in the final evidence report on the ICER website: https:// icer.org/wp-content/uploads/2020/10/ICER_High-Cholesterol_Final-Evidence-Report_030221.pdf. Several key policy recommendations follow: • All stakeholders should ensure that the introduction of new therapies for high cholesterol do not exacerbate existing health inequities and should strive to decrease inequity in the health care system by decreasing cost and access barriers for patients to access effective therapies.
What are the relative effects of bempedoic acid plus maximally tolerated oral lipid therapy vs maximally tolerated oral lipid therapy alone on the following outcomes that inform judgment of the overall long-term value for money of bempedoic acid? What are the relative effects of inclisiran vs PCSK9 inhibitors on the following outcomes that inform judgment of the overall long-term value for money of inclisiran?

Major positive effect
Patients' ability to achieve major life goals related to education, work, or family life 0 1 10 2 0 Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life 0 1 12 1 0 The problem of health inequity 0 0 13 1 0 Care   TABLE 3